June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
KSI-501 is a novel anti-VEGF and anti-IL-6 bispecific biopolymer conjugate to simultaneously address neovascularization and inflammation in retinal diseases
Author Affiliations & Notes
  • Jason Lin
    Kodiak Science, Palo Alto, California, United States
  • Fernando Correa
    Kodiak Science, Palo Alto, California, United States
  • Namrata Prasad
    Kodiak Science, Palo Alto, California, United States
  • Lili Liu
    Kodiak Science, Palo Alto, California, United States
  • Mirna Rodriguez
    Kodiak Science, Palo Alto, California, United States
  • Michael Ngo
    Kodiak Science, Palo Alto, California, United States
  • Kim Williams
    Kodiak Science, Palo Alto, California, United States
  • Janine Lu
    Kodiak Science, Palo Alto, California, United States
  • Rachel Jacobson
    Kodiak Science, Palo Alto, California, United States
  • William Ngo
    Kodiak Science, Palo Alto, California, United States
  • Carrie Lin
    Kodiak Science, Palo Alto, California, United States
  • Xiaojian Huang
    Kodiak Science, Palo Alto, California, United States
  • Long Pham
    Kodiak Science, Palo Alto, California, United States
  • Kiho Song
    Kodiak Science, Palo Alto, California, United States
  • Hong Liang
    Kodiak Science, Palo Alto, California, United States
  • Victor Perlroth
    Kodiak Science, Palo Alto, California, United States
  • Footnotes
    Commercial Relationships   Jason Lin None; Fernando Correa None; Namrata Prasad None; Lili Liu None; Mirna Rodriguez None; Michael Ngo None; Kim Williams None; Janine Lu None; Rachel Jacobson None; William Ngo None; Carrie Lin None; Xiaojian Huang None; Long Pham None; Kiho Song None; Hong Liang None; Victor Perlroth None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1153. doi:
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      Jason Lin, Fernando Correa, Namrata Prasad, Lili Liu, Mirna Rodriguez, Michael Ngo, Kim Williams, Janine Lu, Rachel Jacobson, William Ngo, Carrie Lin, Xiaojian Huang, Long Pham, Kiho Song, Hong Liang, Victor Perlroth; KSI-501 is a novel anti-VEGF and anti-IL-6 bispecific biopolymer conjugate to simultaneously address neovascularization and inflammation in retinal diseases. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1153.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Neovascularization and inflammation play major roles in the pathogenesis of retinal diseases. While monospecific anti-VEGF therapies have been proven to treat neovascularization effectively, they do not address the underlying immune component. Elevated intraocular levels of IL-6 have been implicated in diabetic eye diseases and linked to anti-VEGF treatment resistance in age-related macular degeneration (AMD). We designed KSI-501, a novel VEGF-trap anti-IL-6 bispecific protein conjugated with a high molecular weight biopolymer, which inhibits both signaling pathways with expected long durability.

Methods : A trap-antibody fusion protein was engineered to bind and inhibit both IL-6 and VEGF with the capability of being conjugated to a high molecular weight phosphorylcholine-based biopolymer. Binding affinity and biological activity were investigated using surface plasmon resonance (SPR), Kinetic Exclusion Assay (KinExA), enzyme-linked immunosorbent assay (ELISA), and cell-based assays. Size exclusion chromatography with multi-angle static light scattering (SEC-MALS) and SDS-PAGE were used to determine the antibody:biopolymer conjugation stoichiometry. Negative staining electron microscopy (EM) was used to visualize the VEGF-trap and VEGF complex interaction.

Results : The VEGF-trap anti-IL-6 molecule exhibits high binding affinities to VEGF-A isoforms, VEGF-B, PlGF, PlGF-2, and IL-6. In addition, binding studies show the bispecific molecular design allows for drug engagement with VEGF and IL-6 in an independent and simultaneous manner. Functional assays show the drug inhibits interactions between targets and their respective receptors. KSI-501 exhibits a 1:1 antibody:biopolymer conjugation ratio as supported by SEC-MALS and SDS-PAGE. EM 2D class averaging shows KSI-501 establishes a 1:1 complex with VEGF in which both trap arms engage one VEGF molecule.

Conclusions : KSI-501 has high binding affinity and bioactivity against VEGF and IL-6. Thereby it has the potential to synergistically inhibit both neovascularization and inflammation components underlying the pathogenesis of retinal diseases. Combined with the ABC platform™ which confers enhanced retinal durability, KSI-501 is a promising long-durability therapeutic candidate for vascular and inflammatory diseases.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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